%0 Journal Article
%A Magda F. Morton
%A Terrance D. Barrett
%A Wen Yan
%A Jamie M. Freedman
%A Guy Lagaud
%A Clodagh E. Prendergast
%A Veronica Moreno
%A Jayashree Pyati
%A Katherine Figueroa
%A Lina Li
%A Xiaodong Wu
%A Michele Rizzolio
%A James G. Breitenbucher
%A Kelly McClure
%A Nigel P. Shankley
%T 3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a Novel, Potent, and Selective Cholecystokinin 1 Receptor Antagonist: In Vitro and in Vivo Pharmacological Comparison with Dexloxiglumide
%D 2007
%R 10.1124/jpet.107.124578
%J Journal of Pharmacology and Experimental Therapeutics
%P 562-569
%V 323
%N 2
%X 3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516) is a novel, potent, and selective cholecystokinin (CCK)1-receptor antagonist. In this study, the pharmacology of JNJ-17156516 was investigated both in vitro and in vivo, and the pharmacokinetic profile was evaluated in rats. JNJ-17156516 expressed high-affinity at the cloned human (pKI = 7.96 ± 0.11), rat (pKI = 8.02 ± 0.11), and canine (pKI = 7.98 ± 0.04) CCK1 receptors, and it was also highly selective for the CCK1 receptor compared with the CCK2 receptor across the same species (∼160-, ∼230-, and ∼75-fold, respectively). The high affinity of JNJ-17156516 at CCK1 receptors in vitro was confirmed in radioligand binding studies on fresh human gallbladder tissue (pKI = 8.22 ± 0.05). In a functional in vitro assay of guinea pig gallbladder contraction, JNJ-17156516 behaved as a competitive antagonist, with apKB value of 8.00 ± 0.07. In vivo, JNJ-17156516 produced a parallel, rightward shift in the CCK-8S-evoked contraction of the guinea pig gallbladder. The dose required to shift the CCK-8S dose-response curve was 240 nmol kg–1 i.v. In the anesthetized rat, JNJ-17156516 produced a dose-related decrease in the number of duodenal contractions evoked by infusion of CCK-8S, with an ED50 = 484 nmol kg–1. Pharmacokinetic analysis of JNJ-17156516 in rats, revealed that JNJ-17156516 had a half-life of 3.0 ± 0.5 h and a very high bioavailability (108 ± 10%) in this species. Overall, we have demonstrated that JNJ-17156516 is a high-affinity selective human CCK1 receptor antagonist with good pharmacokinetic properties in rats. The American Society for Pharmacology and Experimental Therapeutics
%U https://jpet.aspetjournals.org/content/jpet/323/2/562.full.pdf